Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The activities of glycolysis and K-+ transport have been studied in slices of Morris hepatoma 3924A incubated under anaerobic conditions in the presence of different concentrations of glucose (1-50 mM). 2. Ouabain-sensitive net transport of K-+ was observed at all glucose concentrations greater than 1 mM; ouabain reduced the rate of glycolysis by about 25% at all glucose concentrations able to support ion transport. 3. The net entry of glucose into the intracellular phase was studied at varying glucose concentrations. The rate of glucose entry was similar to the rate of glucose utilisation by anaerobic glycolysis at medium concentrations of 10 mM and less, but exceeded the rate of glycolysis at 20 mM and above. 4. The glucose entry was not Na-+-dependent and was not inhibited by ouabain. 5. The results suggest (a) that the reduction in glycolytic activity caused by ouabain is not due to an inhibition of glucose transport and (b) that the glucose transport system of this poorly differentiated hepatoma has properties similar to that of normal liver.
 ...
PMID:The control of anaerobic glycolysis by glucose transport and ouabain in slices of hepatoma 3924A. 16 93

Addition of increasing concentrations of glucose to slices of Morris hepatoma 3924A greatly stimulated aerobic lactate production and reduced respiration by 20%. Neither the adenine nucleotide content of the slices nor the calculated rate of adenosine 5'-triphosphate synthesis was altered. Ouabain reduced the rate of O2 uptake (by 20 to 25%) and of aerobic lactate production (by 25 to 50%) without affecting adenine nucleotide contents. The reduction by ouabain of the calculated rate of adenosine 5'-triphosphate synthesis was similar whether the slices were utilizing only endogenous substrate or exogenous glucose also. Raising the medium K+ concentration (and correspondingly reducing Na+) partially overcame the inhibition of ion transport by ouabain and partially restored the rates of respiration and aerobic lactate production toward control levels. Electron microscopic observations of mitochondria within the slices incubated under different conditions showed variations in configuration between "orthodox," "condensed" and degenerating forms. Slices preincubated at 1 degrees showed mitochondria in the condensed form: they were restored to the orthodox configuration during incubation at 38 degrees in oxygenated medium. Oligomycin and glucose enhanced the transition, but ouabain reduced the number of mitochondria undergoing the change. The results suggest that in hepatoma 3924A utilization of adenosine 5'-triphosphate by ion transport exerts a simultaneous control of both respiration and aerobic glycolysis, which is presumably mediated by alterations in the availability of adenosine 5-diphosphate. The mitochondria undergo conformational transitions under conditions likely to affect local availability of adenosine 5'-diphosphate within cell compartments, but the transitions are not all externally added adenosine diphosphate on isolated mitochondria.
 ...
PMID:Interaction of Na+ and K+ transport with aerobic energy metabolism in slices of Morris hepatoma 3924A. 18 27

Ouabain uptake was studied on isolated rat hepatocytes. Hepatocellular uptake of the glycoside is saturable (Km = 348 mumol/l, Vmax = 1.4 nmol/mg cell protein per min), energy dependent and accumulative. Concentrative ouabain uptake is not present on permeable hepatocytes, Ehrlich ascites tumor cells and AS-30D ascites hepatoma cells. There is no correlation between ouabain binding to rat liver (Na+ + K+)ATPase and ouabain uptake into isolated rat hepatocytes. While ouabain uptake is competitively inhibited by cevadine, binding to (Na+ + K+)-ATPase is not affected by the alkaloid. Although the affinities of digitoxin and ouabain to (Na+ + K+)-ATPase are similar, digitoxin is 10000-times more potent in inhibiting [3H]ouabain uptake as compared to ouabain. That binding to (Na+ + K+)-ATPase appears to be no precondition for ouabain uptake was also found in experiments with plasmamembranes derived from Ehrlich ascites tumor cells and AS-30D hepatoma cells. While tumor cell (Na+ + K+)-ATPase is ouabain sensitive, the intact cells are transport deficient. Hepatic ouabain uptake might be related to bile acid transport. Several inhibitors of the bile acid uptake system also inhibit ouabain uptake.
 ...
PMID:Transport functions of the liver. Lack of correlation between hepatocellular ouabain uptake and binding to (Na+ + K+)-ATPase. 298 94

1. This study was designed to determine the role of sodium-potassium adenosine triphosphatase (Na(+)-K(+)-ATPase) in the regulation of human corpus cavernosum smooth muscle contractility by nitric oxide (NO). In addition, we determined if the modulation of Na(+)-K(+)-ATPase activity by NO is dependent on the increase in intracellular cyclic GMP concentration. 2. The effect of NO donors, sodium-nitroprusside (SNP) and S-nitroso-glutathione (S-NO-Glu), and a permeable cyclic GMP analogue, 8-bromo-cyclic GMP, on Na(+)-K(+)-ATPase activity (measured as ouabain-sensitive 86Rb-uptake) was studied in human cultured corpus cavernosum smooth muscle cells (HCCSMC). In addition, the effect of the cyclic GMP lowering agent, methylene blue, on NO-induced increase in Na(+)-K(+)-ATPase activity was studied. 3. SNP (1 microM) caused time-dependent increases in ouabain-sensitive Rb-uptake (33-72%) over 2-20 min in HCCSMC. The stimulation of ouabain-sensitive Rb-uptake by SNP was concentration-dependent (30 and 102% with 0.1 and 1 microM SNP, respectively). Similarly, significant increases in ouabain-sensitive Rb-uptake were obtained with 1 and 10 microM S-NO-Glu. In contrast, incubation of HCCSMC with 8-bromo-cyclic GMP (100 microM) did not increase ouabain-sensitive Rb-uptake. 4. S-NO-Glu induced-increase in intracellular cyclic GMP synthesis, but not the increase in ouabain-sensitive Rb-uptake, was completely inhibited by methylene blue in HCCSMC. 5. The Na(+)-K(+)-ATPase inhibitor, ouabain, caused a concentration-dependent increase in tension (0.5 to 2 fold) in tissues contracted with 15 mM KCl. SNP and S-NO-Glu caused a concentration-dependent relaxation (concentration required to cause half maximal relaxation (ED50) = 0.04 and 0.2 microM, respectively) of HCC strips contracted with 15 mM K+. Ouabain (0.1 to 10 microM) inhibited the response to SNP and S-NO-Glu by shifting the concentration-response curves to the right and preventing full smooth muscle relaxation.6. These results indicate that the activity of Na+-K+-ATPase modulates the contractility of HCC smooth muscle, and that NO stimulates Na+-K+-ATPase activity in HCCSMC independently of its ability to increase the intracellular cyclic GMP concentration. They also suggest that stimulation of Na+-K+-ATPase activity plays an important role in NO-induced relaxation of HCC smooth muscle
 ...
PMID:Possible role of Na(+)-K(+)-ATPase in the regulation of human corpus cavernosum smooth muscle contractility by nitric oxide. 856 49

We have previously reported how the release of fibroblast growth factor-2 (FGF-2) is mediated by shed vesicles. In the present study, we address the question of how newly synthesized FGF-2 is targeted to the budding vesicles. Considering that in vitro cultured Sk-Hep1 hepatocarcinoma cells release FGF-2 and shed membrane vesicles only when cultured in the presence of serum, we added serum to starved cells and monitored intracellular movements of the growth factor. FGF-2 was targeted both to the cell periphery and to the nucleus and nucleolus. Movements toward the cell periphery were not influenced by drugs affecting microtubules, but were inhibited by cytocalasin B. Involvement of actin in FGF-2 trafficking toward the cell periphery was supported by coimmunoprecipitation and immune localization experiments. Colocalization of FGF-2 granules moving to the cell periphery and FM4-64-labelled intracellular lipids were not observed. Ouabain and methylamine, two inhibitors of FGF-2 release, were analyzed for their effects on FGF-2 intracellular localization and on vesicle shedding. Ouabain inhibited FGF-2 movements toward the cell periphery. The FGF-2 content of shed vesicles was therefore reduced. Methylamine inhibited vesicle shedding; in its presence, FGF-2 clustered at the cell periphery, but the rate of its release decreased. FGF-2 targeting to the nucleus and nucleolus was not affected by cytocalasin B, whereas it was inhibited by drugs that modify microtubule dynamics. Neither ouabain, nor methylamine interfered with FGF-2 translocation to the nucleus and nucleolus. FGF-2 targeting to the budding vesicles and to the nucleus and nucleolus is therefore mediated by fundamentally different mechanisms.
 ...
PMID:Intracellular trafficking of endogenous fibroblast growth factor-2. 1831 16

Recent research has shown that the Na(+)/K(+)-ATPase alpha1 subunit is a novel anti-cancer target, which plays pivotal roles in malignant cell ion transport, metabolism, migration and signal transduction. The purpose of the present study was to investigate the anti-cancer effects of ouabain and Na(+)/K(+)-ATPase alpha1 small interfering ribonucleic acid (siRNA) on HepG2 cell proliferation, apoptosis and cell cycle, and to explore the molecular mechanisms. The expression of Na(+)/K(+)-ATPase alpha1 subunit in human hepatocellular carcinoma (HCC), normal liver tissues and human HCC line (HepG2, SMMC-7721 and Bel-7402) has been investigated. Using the ouabain and Na(+)/K(+)-ATPase alpha1 subunit siRNA, which target the Na(+)/K(+)-ATPase, we have evaluated the effects of inhibiting Na(+)/K(+)-ATPase alpha1 in human HepG2 cells with respect to cell proliferation, morphology, cell cycle, impact on intracellular Ca2++, reactive oxygen species (ROS) concentration, and correlated gene expression level on messenger ribonucleic acid (mRNA) and protein. Our data showed that the expression Na(+)/K(+)-ATPase alpha1 subunit in HCC tissues is higher than that in normal liver tissues. Ouabain and Na(+)/K(+)-ATPase alpha1 siRNA could inhibit HepG2 cell proliferation. Ouabain could induce HepG2 cell apoptosis and generate S phase arrest, and siRNA could enhance the anti-cancer effect of ouabain that induced HepG2 cells apoptosis via an intracellular Ca(2+) and ROS increase-mediated, and generated cell cycle S phase arresting by decreasing the CyclinA1/cyclin-dependent kinase 2 (CDK2)/proliferating cell nuclear antigen (PCNA) complex product and increasing the expression of cyclin-dependent kinase inhibitor 1A (P21(CIP1)). We believe that targeting of the Na(+)/K(+)-ATPase alpha1 subunit in human HCC cells could provide new sight into the treatment of HCC.
 ...
PMID:Targeting the Na(+)/K(+)-ATPase alpha1 subunit of hepatoma HepG2 cell line to induce apoptosis and cell cycle arresting. 2046 Jul 49

Recent studies revealed the potential of Na(+)/K(+)-ATPase as a target for anticancer therapy and showed additional modes of action of cardiotonic steroids (CSs), a diverse family of naturally derived compounds, as inhibitors of Na(+)/K(+)-ATPase. The results from epidemiological studies showed significantly lower mortality rates in cancer patients receiving CSs, which sparked interest in the anticancer properties of these drugs. The present study was designed to investigate the anticancer effect of CSs (ouabain or cinobufagin) and to elucidate the molecular mechanisms of CS activity in hepatoma cell lines (HepG2 and SMMC-7721). Ouabain and cinobufagin significantly inhibited cell proliferation by attenuating the phosphorylation of extracellular regulated kinase (ERK) and down-regulating the expression of C-myc. These CSs also induced cell apoptosis by increasing the concentration of intracellular free calcium ([Ca(2+)](i)) and induced S phase cell cycle arrest by down-regulating the expression of Cyclin A, cyclin dependent kinase 2 (CDK2) and proliferating cell nuclear antigen (PCNA) as well as up-regulating the expression of cyclin dependent kinase inhibitor 1A (p21(CIP1)). Overexpression of ERK reversed the antiproliferation effect of ouabain or cinobufagin in HepG2 and SMMC-7721 cells. Currently, the first generation of CS-based anticancer drugs (UNBS1450 and Anvirzel) are in Phase I clinical trials. These data clearly support their potential use as cancer therapies.
 ...
PMID:Cardiotonic steroids attenuate ERK phosphorylation and generate cell cycle arrest to block human hepatoma cell growth. 2121 1